Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388955%3A_____%2F21%3A00549116" target="_blank" >RIV/61388955:_____/21:00549116 - isvavai.cz</a>
Result on the web
<a href="http://hdl.handle.net/11104/0325130" target="_blank" >http://hdl.handle.net/11104/0325130</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/biology10121240" target="_blank" >10.3390/biology10121240</a>
Alternative languages
Result language
angličtina
Original language name
Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant
Original language description
In this work, we investigate the β-barrel of superoxide dismutase 1 (SOD1) in a mutated form, the isoleucine 35 to alanine (I35A) mutant, commonly used as a model system to decipher the role of the full-length apoSOD1 protein in amyotrophic lateral sclerosis (ALS). It is known from experiments that the mutation reduces the stability of the SOD1 barrel and makes it largely unfolded in the cell at 37 degrees Celsius. We deploy state-of-the-art computational machinery to examine the thermal destabilization of the I35A mutant by comparing two widely used force fields, Amber a99SB-disp and CHARMM36m. We find that only the latter force field, when combined with the Replica Exchange with Solute Scaling (REST2) approach, reproduces semi-quantitatively the experimentally observed shift in the melting between the original and the mutated SOD1 barrel. In addition, we analyze the unfolding process and the conformational landscape of the mutant, finding these largely similar to those of the wildtype. Nevertheless, we detect an increased presence of partially misfolded states at ambient temperatures. These states, featuring conformational changes in the region of the β-strands β4−β6, might provide a pathway for nonnative aggregation.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10403 - Physical chemistry
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biology
ISSN
2079-7737
e-ISSN
2079-7737
Volume of the periodical
10
Issue of the periodical within the volume
12
Country of publishing house
CH - SWITZERLAND
Number of pages
12
Pages from-to
1240
UT code for WoS article
000736337000001
EID of the result in the Scopus database
2-s2.0-85120805780